Enhanced compositions for pulmonary arterial hypertension

Abstract

The present invention relates immediate-release tablet compositions comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients.

Description

[0001] ENHANCED COMPOSITIONS FOR PULMONARY ARTERIAL HYPERTENSION Field of Invention

[0002] The present invention relates immediate-release tablet compositions comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients.

[0003] Background of the Invention

[0004] Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition that significantly reduces life expectancy due to its high incidence of severe complications. The disease often leads to right heart failure and, eventually, death, primarily due to increased pulmonary vascular resistance and right ventricular dysfunction. Additionally, individuals with PAH face a heightened risk of hospitalization and reduced quality of life. Pharmacological treatments are commonly utilized as first- or second-line therapies, either as monotherapy or in combination with other agents, depending on disease severity and progression. These therapies are crucial in managing symptoms and slowing disease progression.

[0005] Pulmonary arterial hypertension (PAH) is a type of high blood pressure that affects the arteries in the lungs and the right side of the heart. It is characterized by the narrowing and stiffening of the small pulmonary arteries, which leads to increased resistance to blood flow and elevated pressure in the pulmonary circulation. This condition forces the right ventricle to work harder to pump blood through the lungs, eventually causing right ventricular hypertrophy and heart failure.

[0006] Macitentan is an endothelin receptor antagonist (ERA) and is used for the treatment of pulmonary arterial hypertension (PAH). It is currently approved for improving exercise capacity and delaying disease progression in patients with PAH. The chemical name of macitentan is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide and its chemical structure is shown below.

[0007]

[0008] Macitentan

[0009] Tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor and is therefore used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension (PAH). It is currently approved for improving erectile function, relieving urinary symptoms associated with BPH, and managing the symptoms of PAH. The chemical name of tadalafil is (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione and its chemical structure is shown below.

[0010]

[0011] Tadalafil

[0012] The particle size of components in a tablet formulation significantly influences the tablet's physical and functional properties, An optimal particle size ensures that the ingredients have sufficient surface area to dissolve efficiently while maintaining good flowability during the manufacturing process, However, excessively fine particles can lead to poor flow characteristics, causing difficulties in processing and potentially resulting in content uniformity issues. Conversely, overly large particles may slow down the dissolution rate of the active pharmaceutical ingredient, potentially reducing its bioavailability. Therefore, carefully optimizing particle size is crucial to achieving the desired balance between manufacturing efficiency and the tablet's dissolution performance.

[0013] In view of the foregoing, there is a need to improve stability, improves dissolution and high patient compliance in compositions comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient. The present invention provides a solution to these problems by providing novel compositions comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients. These solutions will be described in detail.

[0014] Brief Description of the Invention

[0015] The present invention provides a tablet composition prepared by spray granulation comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient, characterized in that d (90) particle size of tadalafil is less than 15 µm and d (90) particle size of macitentan is less than 15 µm.

[0016] A tablet composition comprises excipients wherein the excipients can be selected from diluents, binders, solvents, lubricants, glidants, disintegrants, antioxidants, solubility increasing agents, preservatives, surfactants, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent and mixtures thereof.

[0017] A tablet composition in present invention wherein the surfactant is sodium lauryl sulphate.

[0018] A tablet composition in present invention, wherein the amount of sodium lauryl sulphate can be between 0.20-0.40 % (w / w).

[0019] A spray granulation process for preparing tablet composition comprising the steps of: a. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant,

[0020] b. Adding, sieving one or more diluent, one or more disintegrant,

[0021] c. Performing wet granulation by spraying the granulation suspension obtained in step a onto the step b mixture,

[0022] d. Drying, sieving and obtaining sub-batch granule part containing Tadalafil, e. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant,

[0023] f. Adding, sieving and drying macitentan, one or more diluent, one or more disintegrant,

[0024] g. Performing wet granulation by spraying the granulation suspension obtained in step e onto the step f mixture,

[0025] h. Drying, sieving and obtaining sub-batch granule part containing macitentan i. Mixing step d and step h mixtures,

[0026] j. Compressing tablets

[0027] A tablet composition according to any one of the proceeding claims for use in the treatment of pulmonary arterial hypertension.

[0028] Detailed Description of the Invention

[0029] The aspects and disclosures according to the present invention, in particular the compositions, methods and uses, refer to compositions comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient.

[0030] A tablet composition comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients, characterized in that a d (90) particle size of tadalafil is less than 15 pm and a d (90) particle size of macitentan is less than 15 µm.

[0031] A tablet composition is prepared by spray granulation comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients, characterized in that a d (90) particle size of tadalafil is less than 15 pm and a d (90) particle size of macitentan is less than 15 µm.

[0032] The value d (90) refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d (90) value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, the d (90) describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. In one embodiment a pharmaceutical composition according to present invention, composition can be a form of capsule, tablet, mini tablet, multilayer tablet or film coated tablet. Preferably a pharmaceutical composition is a form of a tablet or film coated tablet, more preferably is film coated tablet.

[0033] The present invention provides a pharmaceutical composition comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient.

[0034] The present invention provides tablet composition comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient. In the present invention, the amount of binder can be between 0.1 % and 1.5 % of the total composition. In the present invention, the binder can be hydroxypropyl cellulose and / or povidone. In an amount of hydroxypropyl cellulose can be between 0.1% to 0.75 %, preferably 0.2% to 0.5%, more preferably 0.3% to 0.4%. In an amount of povidone can be between 0.1% to 0.75 %, preferably 0.15% to 0.5%, more preferably 0.2% to 0.4%.

[0035] In a tablet composition, the inner layer refers to the core of the tablet, which typically comprises the active pharmaceutical ingredient and may also include excipients that help in controlling the release or stability of the drug.

[0036] The outer layer (or coating) is the external part of the tablet, often designed to protect the inner layer from environmental factors, enhance the tablet's appearance, or control the release profile of the drug (e.g., delayed, immediate or sustained release).

[0037] In one embodiment, inner layer can be comprised, tadalafil and macitentan as active ingredients, disintegrants, binders, surfactants, diluents and solvents.

[0038] In one embodiment, outer layer can be comprised, tadalafil and macitentan as active ingredients, disintegrant, lubricant and coating materials.

[0039] In one embodiment, outer layer can be comprised, disintegrant, lubricant and coating materials.

[0040] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0041] Preferably, the present invention relates to a pharmaceutical composition comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipients wherein the excipients are selected from the group including, but are not limited to diluents, lubricants, glidants, disintegrants, antioxidants, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent, mixtures thereof and other materials known to one of ordinary skill in the art and the mixtures thereof.

[0042] According to one embodiment of the present invention, the amount of tadalafil is present between 5.0% and 15.0% by weight in the total composition. Preferably, the amount of tadalafil is between 7.50% and 12.50% by weight in the total composition. More preferably, the amount of tadalafil is between 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 10.10%, 10.20%, 10.30%, 10.40%, 10.50%, 10.60%, 10.70%, 10.80%, 10.90%, 11.00%, 11.10%, 11.20%, 11.30%, 11.40%, 11.50%, 11.60%, 11.70%, 11.80%, 11.90%, 12.00%, 12.10%, 12.20%, 12.30%, 12.40% or 12.50% by weight in the total composition.

[0043] According to one embodiment of the present invention, the amount of macitentan is present between 1.00% and 5.00% by weight in the total composition. Preferably, the amount of macitentan is between 2.00% and 4.00% by weight in the total composition. More preferably, the amount of macitentan is between 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90% or 4.00 by weight in the total composition.

[0044] Lubricants are important excipients in tablet compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from sticking to the equipment, ensuring a smooth and efficient production process. Lubricants improve the flow of the tablet mixture through the machinery, enhancing the uniformity and consistency of the final product.

[0045] Commonly used lubricants in tablet compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and polyethylene glycol (PEG). In preferred embodiment in the present invention amount of lubricant can be between 0.25-1.5% (w / w).

[0046] In preferred embodiment in present invention lubricant can be magnesium stearate. In preferred embodiment present invention amount of magnesium stearate can be between 0.25-1.5% (w / w).

[0047] In tablet compositions, surfactants are used to improve the wetting properties and enhance the solubility or dissolution rate of active ingredients during the manufacturing processes. These substances are added to formulations to ensure that active ingredients are properly dispersed and dissolved during tablet or capsule production, improving bioavailability and ensuring consistent therapeutic effects. Surfactants are particularly important in formulations with poorly soluble active ingredients, which often have limited bioavailability. In a preferred embodiment of the present invention, the amount of surfactant can be between 0.001-0.5% (w / w).

[0048] Commonly used surfactants in tablet compositions include sodium lauryl sulfate, polysorbate 80, sorbitan esters, lecithin, and certain bile salts. These surfactants are added to improve the wetting properties and enhance the solubility or dissolution rate of active ingredients.

[0049] In a preferred embodiment, the surfactant in the present invention compositions can be polysorbate 80 and / or sodium lauryl sulphate. In a preferred embodiment of the present invention, the total amount of polysorbate 80 and sodium lauryl sulphate can be between 0.01-0.5% (w / w).

[0050] In preferred surfactant can be sodium lauryl sulphate. In preferred compositions of present invention sodium lauryl sulphate amount in total composition 0.20-0.40 % (w / w). Sodium lauryl sulphate increases tadalafil dissolution rate these quantities in this range. Diluents are important excipients in tablet compositions, primarily used to increase the bulk of the tablet, making it practical for handling and administration. They help achieve the desired tablet size and weight, ensuring accurate dosing and ease of swallowing. Diluents improve the physical properties of the tablet, enhancing the uniformity and consistency of the final product.

[0051] Commonly used diluents in tablet compositions include lactose, microcrystalline cellulose, dicalcium phosphate, mannitol, and starch. In a preferred embodiment of the present invention, the amount of diluent can be between 10.00-90.00% (w / w), depending on the formulation requirements.

[0052] In a preferred embodiment of the present invention, the diluent can be microcrystalline cellulose and / or lactose monohydrate. The amount of microcrystalline cellulose and / or lactose monohydrate can be adjusted appropriately to achieve the desired tablet properties, typically ranging from 40.00-80.00% (w / w).

[0053] Disintegrants are important excipients in tablet compositions, primarily used to facilitate the rapid breakup of the tablet upon ingestion. They promote the disintegration of the tablet into smaller fragments in the gastrointestinal tract, enhancing the dissolution and bioavailability of the active ingredients. Disintegrants ensure that the tablet dissolves properly, allowing for timely release and absorption of the medication.

[0054] Commonly used disintegrants in tablet compositions include croscarmellose sodium, sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose, alginic acid, and powdered cellulose. In a preferred embodiment of the present invention, the amount of disintegrant can be between 1-10% (w / w), depending on the specific formulation requirements.

[0055] In a preferred embodiment of the present invention, the disintegrant can be croscarmellose sodium. The total amount of low substituted hydroxypropyl cellulose, crospovidone and sodium starch glycolate can be adjusted appropriately to achieve the desired disintegration properties, typically ranging from 2-8% (w / w).

[0056] The technical problem in the present invention can be expressed as obtaining optimum dissolution rates for final product. In solving this problem, the D90 value for active substances of tadalafil and macitentan should be used in the appropriate range. Improvement of dissolution rates is critical.

[0057] The inventors suprisingly have found that the tablet compositions comprising tadalafil, macitentan, hydroxypropyl cellulose as a binder and one or more pharmaceutically acceptable excipient wherein a d (90) particle size of tadalafil less than 15 pm and a d (90) particle size of less than 15 pm improve stability, improves dissolution and high patient compliance for tablet compositions.

[0058] In further embodiment tablet compositions in present invention can be comprised of coating.

[0059] A spray granulation process for preparing tablet composition comprising the steps of: a. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant,

[0060] b. Adding, sieving one or more diluent, one or more disintegrant,

[0061] c. Performing wet granulation by spraying the granulation suspension obtained in step a onto the step b mixture,

[0062] d. Drying, sieving and obtaining sub-batch granule part containing Tadalafil, e. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant, f. Adding, sieving and drying macitentan, one or more diluent, one or more disintegrant,

[0063] g. Performing wet granulation by spraying the granulation suspension obtained in step e onto the step f mixture,

[0064] h. Drying, sieving and obtaining sub-batch granule part containing Macitentan i. Mixing step d and step h mixtures,

[0065] j. Compressing tablets

[0066] In other aspect of a pharmaceutical composition of the present invention for use in use in the treatment of pulmonary arterial hypertension.

[0067] EXAMPLES EXAMPLE 1

[0068] In one embodiment, present invention compositions can be as follows:

[0069]

[0070] In other aspect of the present invention a process for preparing a tablet composition can be comprises below steps: a. Preparing a granulation suspension comprising tadalafil, purified water, hydroxypropyl cellulose and sodium lauryl sulphate,

[0071] b. Adding, sieving lactose monohydrate, crospovidone, microcrystalline cellulose and low substituted hydroxypropyl cellulose,

[0072] c. Performing wet granulation by spraying the granulation suspension obtained in step a onto the step b mixture,

[0073] d. Drying, sieving and obtaining sub-batch granule part containing Tadalafil, e. Preparing a granulation suspension comprising tadalafil, purified water, povidone and polysorbate 80,

[0074] f. Adding, sieving and drying macitentan, lactose monohydrate, sodium starch glycolate, microcrystalline cellulose,

[0075] g. Performing wet granulation by spraying the granulation suspension obtained in step e onto the step f mixture,

[0076] h. Drying, sieving and obtaining sub-batch granule part containing Macitentan, i. Mixing step d and step h mixtures,

[0077] j. Compressing tablets,

[0078] k. Coating tablets with coating materials.

[0079] Example 2

[0080] In one embodiment, present invention compositions can be as follows:

[0081]

[0082]

[0083] In other aspect of the present invention a process for preparing a tablet composition can be comprises below steps:

[0084] a. Preparing a granulation suspension comprising tadalafil, purified water, hydroxypropyl cellulose and sodium lauryl sulphate,

[0085] b. Adding, sieving lactose monohydrate, crospovidone, microcrystalline cellulose and low substituted hydroxypropyl cellulose,

[0086] c. Performing wet granulation by spraying the granulation suspension obtained in step a onto the step b mixture,

[0087] d. Drying, sieving and obtaining sub-batch granule part containing Tadalafil, e. Preparing a granulation suspension comprising tadalafil, purified water, povidone and polysorbate 80,

[0088] f. Adding, sieving and drying macitentan, lactose monohydrate, sodium starch glycolate, microcrystalline cellulose,

[0089] g. Performing wet granulation by spraying the granulation suspension obtained in step e onto the step f mixture,

[0090] h. Drying, sieving and obtaining sub-batch granule part containing Macitentan, i. Mixing step d and step h mixtures,

[0091] j. Compressing tablets,

[0092] k. Coating tablets with coating materials. Dissolution Results

[0093] Four sample sets were prepared for dissolution measurements. The results were obtained as in the table below.

[0094]

[0095] Sample 1 comprises macitentan, tadalafil wherein D90 value of tadalafil is below 15 micron (D90: 10 micron).

[0096] Sample 2 comprises macitentan, tadalafil wherein D90 value of tadalafil is above 15 micron (D90: 20 micron).

[0097] Sample 1 has provided more favorable values compared to Sample 2. The use of 10 micron for D90 value of tadalafil, has improved and contributed to better dissolution results.

[0098]

[0099] Sample 3 comprises macitentan, tadalafil wherein D90 value of macitentan is below 15 micron (10 micron).

[0100] Sample 2 comprises macitentan, tadalafil wherein D90 value of macitentan is above 15 micron (20 micron).

[0101] Sample 1 has provided more favorable values compared to Sample 2. The use of 10 micron for D90 value of macitentan, has improved and contributed to better dissolution results.

Claims

CLAIMS1. A tablet composition prepared by spray granulation comprising tadalafil, macitentan and one or more pharmaceutically acceptable excipient,characterized in that d (90) particle size of tadalafil is less than 15 µm and d (90) particle size of macitentan is less than 15 µm.

2. A tablet composition according to claim 1, wherein the excipients are selected from diluents, binders, solvents, lubricants, glidants, disintegrants, antioxidants, solubility increasing agents, preservatives, surfactants, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent and mixtures thereof.

3. A tablet composition according to claim 2, wherein the surfactant is sodium lauryl sulphate.

4. A tablet composition according to claim 3, wherein the amount of sodium lauryl sulphate is between 0.20-0.40 % (w / w).

5. A spray granulation process for preparing tablet composition according to claim 1, comprising the steps of:a. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant,b. Adding, sieving one or more diluent, one or more disintegrant,c. Performing wet granulation by spraying the granulation suspension obtained in step a onto the step b mixture,d. Drying, sieving and obtaining sub-batch granule part containing Tadalafil, e. Preparing a granulation suspension comprising tadalafil, purified water, a binder and surfactant,f. Adding, sieving and drying macitentan, one or more diluent, one or more disintegrant,g. Performing wet granulation by spraying the granulation suspension obtained in step e onto the step f mixture,h. Drying, sieving and obtaining sub-batch granule part containing Macitentan, i. Mixing step d and step h mixtures,j. Compressing tablets,6. A tablet composition according to any one of claims 1-4 for use in the treatment of pulmonary arterial hypertension.

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